tbuckley/cabot-search huggingface dataset:
Abstract 5404: Predicting protein receptor status from H&amp;E-stained images in breast cancer
Authors: Geongyu Lee, Chungyeul Kim, Tae-Yeong Kwak, Sun Woo Kim, Hyeyoon Chang
Journal: Cancer Research (2023)

Abstract Correct prediction of cancer molecular subtype plays a very important role in determining the treatment of cancer patients. In determining the molecular subtype of breast cancer, protein receptors such as estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor type 2 (HER2) are used as key factors. These protein receptors also play an important role in determining the treatment method or predicting the prognosis of breast cancer. To confirm this, a test should be performed by immunohistochemical (IHC) staining. In this study, we investigated the morphological relationship between the molecular subtypes and hematoxylin and eosin (H&amp;E) stained whole slide images (WSIs) without IHC stained images, and performed an experiment to evaluate that the protein receptors can be predicted by these morphological features. The TCGA-BRCA data were utilized in this study. There were 728 cases out of the total 1097 cases where the IHC status for ER, PR, and HER2 was either positive or negative. Each individual case is scanned using different scanners and magnifications. In some cases with multiple slides, we use only the first scanned image. The entire WSI was randomly split into 3:1:1, and used for training, tuning, and test, respectively. Individual WSIs was tiled into 1024 × 1024 patches for this study. The multi-task deep learning model predicts the protein receptor status of individual patches. In this study, a confidence measure was added to remove the uncertainty of the deep learning model. When learning WSIs, patches of less than 70% based on these confidence scores did not affect WSIs. Specifically, when learning morphological features, we used strong augmentation such as grayscale, gaussian blur, color jitter, and posterization to ensure that predictions were not biased by color alone. Based on individual patches, ER accuracy of 76%, PR accuracy of 65%, and HER2 accuracy of 79% are shown. As a result of prediction by majority voting on WSI images through patch predicted results, ER accuracy of 74.6% PR accuracy of 66%, and HER2 accuracy of 76.6% Through this study, it was confirmed that the sufficiently trained deep learning model predicted ER, PR, and HER2, which are important factors of molecular subtype, relatively well. Through this, it was found that there was some correlation between morphological characteristics and molecular subtypes in H&amp;E stained WSIs. If more data are collected through future experiments, a molecular subtype prediction model can be developed. Citation Format: Geongyu Lee, Chungyeul Kim, Tae-Yeong Kwak, Sun Woo Kim, Hyeyoon Chang. Predicting protein receptor status from H&amp;E-stained images in breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5404.
Abstract 548: The microRNA-10b targeted therapeutic, TTX-MC138, is effective in preclinical pancreatic adenocarcinoma
Authors: Subrata Ghosh, Douglas Lazarus, Neil Robertson, Edward Crosier, Peter Liu, Zdravka Medarova
Journal: Cancer Research (2023)

Abstract Non-coding RNAs, such as miRNAs, represent promising targets for cancer therapy, given their role as critical players in oncogenic processes, including tumor initiation and progression, metastasis and therapeutic resistance. We and others demonstrated that miRNA-10b is a critical driver of tumor cell viability, especially in the metastatic setting. Based on this discovery, it became feasible to treat established metastatic cancer by inhibiting miR-10b. This was accomplished using a therapeutic, termed TTX-MC138, composed of antagomirs against miR-10b, conjugated to dextran-coated iron oxide nanoparticles. In our previous studies in murine models of metastatic breast cancer, we demonstrated the effectiveness of TTX-MC138 at preventing and eliminating existing metastases. Here, we describe the application of TTX-MC138 for the treatment of pancreatic adenocarcinoma. TTX-MC138 was administered weekly via intravenous injection into mice bearing orthotopic xenografts derived from human pancreatic adenocarcinoma cells. Tumor burden was measured by in vivo bioluminescence imaging. Animal survival, body weight, and tumor and metastatic burden at necropsy were also analyzed. Serum and tumor miR-10b expression, as well as global gene expression using RNA-seq were assessed to provide insight into target engagement and molecular function. Animals treated with vehicle or gemcitabine served as controls. Tumor growth rate was found to be significantly lower in animals treated with TTX-MC138 vs controls (p &amp;lt; 0.0001 for TTX-MC138 vs. PBS and vs. gemcitabine). Importantly, 40% of the animals treated with TTX-MC138 regressed their tumors completely as measured by bioluminescence imaging. Treatment continued for 10 weeks, after which the responding mice were monitored for disease recurrence without treatment for an additional 10 weeks. The animals showed evidence of continued weight gain and durable survival. They were sacrificed 10 weeks after treatment was discontinued, despite no evidence of morbidity, to perform necropsy. No tumors or metastases were found at the time of sacrifice. Gene expression analysis confirmed target engagement and molecular mechanism of action. Against the background of our earlier work, these studies provide further evidence of the potential of TTX-MC138 for cancer therapy and expand its relevance beyond metastatic breast cancer to also include pancreatic adenocarcinoma. Citation Format: Subrata Ghosh, Douglas Lazarus, Neil Robertson, Edward Crosier, Peter Liu, Zdravka Medarova. The microRNA-10b targeted therapeutic, TTX-MC138, is effective in preclinical pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 548.
Abstract 3818: Isoandrographolide derivative, (3,19)-4-Bromobenzylidene-isoandrographolide induces apoptosis and causes loss of mitochondrial membrane potential in ER positive Breast cancer
Authors: Balasubramanyam Karanam, Nitesh Tamang, Yashwanth Inabathina, Sai Kiran Mavileti, Lakshminath Sripada, Srinivas Nanduri, Nageswara Rao Golakoti
Journal: Cancer Research (2023)

Abstract Natural product, Andrographolide.is diterpene lactone extracted from Andrographis paniculata. In traditional form of medicine, it is being used in India, China and Malaysia for treating various diseases. While in the last two decades there are many reports on andrographolides and its derivatives with various biological activities such as anti-cancer and anti-inflammatory. We synthesized compounds along with isoandrographolide were characterized and tested for their anticancer activity against 60 cancer cell line at NCI. Most compounds were found to be active against leukemia and breast cancer with (3,19)-4-Bromobenzylidene-isoandrographolide having best growth inhibition of 76.90% and 87.54% against leukemia (MOLT-4) and breast cancer (BT-549) respectively. Upon further testing compound (3,19)-4-Bromobenzylidene-isoandrographolide was found to be more activate than the tamoxifen against MCF-7. Compound (3,19)-4-Bromobenzylidene-isoandrographolide arrested cell cycle at G1-Phase of MCF-7 and was observed to be inducing apoptosis and loss of mitochondrial membrane potential. We discuss our studies on crystal structure, cell cycle progression assay, apoptotic studies on ER-positive breast cancer MCF-7. Citation Format: Balasubramanyam Karanam, Nitesh Tamang, Yashwanth Inabathina, Sai Kiran Mavileti, Lakshminath Sripada, Srinivas Nanduri, Nageswara Rao Golakoti. Isoandrographolide derivative, (3,19)-4-Bromobenzylidene-isoandrographolide induces apoptosis and causes loss of mitochondrial membrane potential in ER positive Breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3818.
Abstract 6475: Compatibility of chatbot-based mobile and paper-based FFQs in participants with colorectal or gastric cancer screening
Authors: Eui Yeon Lim, Yun Jeong Lim, Sang Hoon Kim, Woongsup Kim, Jung Eun Lee
Journal: Cancer Research (2023)

Abstract Background: The food frequency questionnaire (FFQ) is the most commonly used method to assess the usual diet of groups and individuals. Paper or electronic FFQ consists of frequencies and portion sizes of foods and beverages. We developed a chatbot-based mobile FFQ, by embedding the validated FFQs in KakaoTalk, Korea’s most popular mobile messenger. We examined the compatibility of the paper and chatbot-based mobile FFQs in participants who underwent cancer screening endoscopy. Method: A total of 50 men and 45 women aged 24 to 79 were recruited from Dongguk University Ilsan Hospital between April and August 2022. Participants underwent gastroscopy or colonoscopy for cancer screening. They completed both the paper and chatbot-based mobile FFQs. Log-transformed intakes of energy and nutrients were compared using the Pearson correlation coefficient. We also calculated the Cohen’s Kappa coefficients and evaluated Bland-Altman plots and the percent agreement from cross-classification to assess the compatibility. Results: The Pearson correlation coefficients of energy and energy-adjusted nutrients ranged from 0.74 (niacin) to 0.90 (vitamin A), and the median of coefficients was 0.85. Cohen’s kappa coefficient ranged from 0.56 (sodium) to 0.75 (n-6 fatty acid). In the Bland-Altman plots, most data were located between the lower and upper limits of agreement. The percentages of participants classified into the same and adjacent quartiles were between 88% and 98% for energy-adjusted nutrients. Conclusions: Our study suggests a good compatibility of paper and chatbot-based mobile FFQs. The chatbot-based mobile FFQ may provide comparable intake rankings and be used to evaluate the association between dietary intake and disease risk in longitudinal studies. Citation Format: Eui Yeon Lim, Yun Jeong Lim, Sang Hoon Kim, Woongsup Kim, Jung Eun Lee. Compatibility of chatbot-based mobile and paper-based FFQs in participants with colorectal or gastric cancer screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6475.
Abstract 6442: Role of TWEAK-Fn14 axis in driving immunosuppression in glioblastoma multiforme
Authors: Angad Beniwal, Ryan Eghlimi, Kenneth D. Alexander, Mylan R. Blomquist, Nhan Tran
Journal: Cancer Research (2023)

Abstract Cellular heterogeneity within glioblastoma multiforme (GBM) is a key driver of resistance to standard-of-care therapeutic approaches such as DNA damage (temozolomide, TMZ), angiogenesis inhibition (Bevacizumab, BM), radiation necrosis, and surgical resection. As such, understanding and targeting heterogeneous tumor-associated populations is a critical aim of ongoing GBM research. Central nervous system (CNS) resident microglia constitute significant percentages of primary GBM samples, often up to 50% of bulk tumor. Additionally, glioblastoma-associated microglia have been implicated in intra-tumoral immunosuppression, and are thus a key barrier to successful implementation of immunotherapies that seek to enhance T-cell mediated anti-tumoral cytotoxicity. As such, insight into targetable pathways that upregulate immunosuppressive cytokines within GBM-associated microglia is necessary for overcoming immuno-therapeutic failure. Here, we identify expression of the cytokine TWEAK (TNFSF12) and its receptor Fn14 (TNFRSF12A) within the myeloid compartment of primary GBM samples via scRNA-seq. Furthermore, we demonstrate TWEAK-mediated reprogramming of GBM-associated microglia towards an immunosuppressive phenotype capable of inhibiting CD8+ T cell activation and proliferation. These findings unveil a potent, targetable axis of immunosuppression within GBM and are thus an exciting step towards enhancing efficacy of existing T-cell based anti-cancer strategies for GBM patients. Citation Format: Angad Beniwal, Ryan Eghlimi, Kenneth D. Alexander, Mylan R. Blomquist, Nhan Tran. Role of TWEAK-Fn14 axis in driving immunosuppression in glioblastoma multiforme [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6442.
Abstract 1217: The <i>FAM72</i> gene family promotes cancer development by disabling the base excision repair system
Authors: Yuqing Feng, Bhupesh Thakur, Jeffery Bruce, Sami Mamand, Melika Shirdarreh, Matthew Wong, Jennifer Silvester, Ming Han, Mohammad Kashem, Amin Zia, David Cescon, Tervor Pugh, Rossanna C. Pezo, Alberto Martin
Journal: Cancer Research (2023)

Abstract Genetic lesions are central contributors to cancer development and progression, and understanding the sources of these lesions will provide a better understanding of the mechanisms of carcinogenesis. Our previous work showed that the uncharacterized murine Fam72a gene promotes mutagenic DNA repair during antibody maturation by causing the degradation of Uracil DNA glycosylase 2 (UNG2), a component of the base excision repair (BER) system. Humans encode four almost identical paralogues of FAM72 called FAM72A-D, which are absent in all other mammalian genomes, including those of non-human primates. The role of these four paralogues in human biology is unknown. Intriguingly, a previous report showed that FAM72A is over-expressed in many cancers. Since FAM72A promotes mutagenesis by degradation of UNG2, we hypothesized that overexpression of the FAM72 gene family might promote cancer development and progression. Here we show that FAM72A-D is overexpressed in many human cancers and inversely correlates with UNG2 protein levels in tumorigenic tissue. However, FAM72A but not FAM72B-D causes degradation of UNG2. Consistent with this effect, FAM72 expression correlates with a higher mutation load in many tumor types. Since genetic mutations are associated with cancer development and progression, we tested whether FAM72 expression is associated with disease outcomes. Indeed, we found that high FAM72 expression was associated with poorer survival in several cancers. To directly test if Fam72a is sufficient to promote cancer, we generated transgenic mice that overexpress Fam72a in multiple tissues. We observed that Fam72a overexpression promotes increased colonic polyps in the Apcmin background compared to controls. These data show that the novel FAM72 gene family are drivers of cancer development in both mice and humans and advances our understanding of the underlying molecular mechanisms that precipitate cancer development and progression. This work is supported by a grant from the CIHR (PJT-180269). Citation Format: Yuqing Feng, Bhupesh Thakur, Jeffery Bruce, Sami Mamand, Melika Shirdarreh, Matthew Wong, Jennifer Silvester, Ming Han, Mohammad Kashem, Amin Zia, David Cescon, Tervor Pugh, Rossanna C. Pezo, Alberto Martin. The FAM72 gene family promotes cancer development by disabling the base excision repair system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1217.
Abstract 1008: A novel biomarker and therapeutic target for early pancreatic cancer
Authors: Min Seok Park, Kyung Hee Jung, Sang Eun Kim, Yun Ji Lee, Sunghyouk Park, Soon-Sun Hong
Journal: Cancer Research (2023)

Abstract Purpose: Pancreatic cancer (PC) has a grim prognosis, and an early diagnostic biomarker has been highly desired. The molecular link between diabetes and PC has not been well established. Methods: Bioinformatics screening was performed for a serum PC marker. Experiments in cell lines (5 PC and 1 normal cell lines), mouse models, and human tissue staining (37 PC and 10 normal cases) were performed to test asprosin production from PC. Asprosin’s diagnostic performance was tested with serums from multi-center cohorts (347 PC, 209 normal, and 55 additional diabetic patients) and evaluated according to PC status and stages which was compared with that of CA19-9. Results: Asprosin, a diabetes-related hormone, was found from the bioinformatics screening, and its production from PC was confirmed. Serum asprosin levels from multi-center cohorts yielded an age-adjusted diagnostic area under the curve (AUC) of 0.987 (95% confidence interval [CI] = 0.961 to 0.997), superior to that of CA19-9 (AUC = 0.876, 95% CI = 0.847 to 0.905), and a cut-off of 7.18 ng/mL, at which the validation set exhibited a sensitivity of 0.957 and a specificity of 0.924. Importantly, the performance was maintained in early stage PC, consistent with the tissue staining. A slightly lower performance against additional diabetic patients (n = 55) was restored by combining asprosin and CA19-9 (AUC = 0.985, 95% CI = 0.975 to 0.995). Conclusion: Asprosin is presented as an early-stage PC serum marker that may provide clues for PC-induced diabetes. Larger prospective clinical studies are warranted to solidify its utility. Citation Format: Min Seok Park, Kyung Hee Jung, Sang Eun Kim, Yun Ji Lee, Sunghyouk Park, Soon-Sun Hong. A novel biomarker and therapeutic target for early pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1008.
Abstract 5489: Synergistic activity of SCD1 blockade in combination with tyrosine kinase inhibitors lenvatinib and cabozantinib in hepatocellular carcinoma (HCC)
Authors: Justyna J. Gleba, Aylin Alasonyalilar-Demirer, Matthew L. Pawlush, Ahmet Bilgili, Peyton G. Hickman, Kabir Mody, Lewis R. Roberts, Steven R. Alberts, Mark J. Truty, Tushar C. Patel, Han W. Tun, John A. Copland
Journal: Cancer Research (2023)

Abstract Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Tyrosine kinase inhibitors (TKIs) are approved as a first-line treatment for unresectable HCC. Lenvatinib and cabozantinib are two of the most used TKIs, but the therapeutic duration is limited due to the development of drug resistance. Therefore, understanding the mechanisms of resistance and combining TKIs with other drugs antagonizing resistance should lead to antitumor synergy, eliminating drug resistance. It turns out that the simultaneous use of TKIs together with an inhibitor of stearoyl-CoA desaturase 1 (SCD1) prevents the development of drug resistance, leading to a durable response. SCD1 is the enzyme responsible for de novo fatty acid (FAs) synthesis, converting saturated fatty acids (SFAs) into monounsaturated fatty acids (MUFAs). MUFAs are an alternative energy source to glucose, integral to cellular membranes, and prevent endoplasmic reticulum (ER) stress and other signaling pathways. In our laboratory, we developed a novel, highly specific SCD1 inhibitor - SSI-4. We have tested the biological activity of SSI-4 against different HCC cell lines and patient-derived xenografts (PDX) mouse models. Of the twelve tested HCC cell lines, four were highly sensitive to SSI-4 (IC50 1-50 nM). Other cell lines showed moderate or no sensitivity to SSI-4. We tested the concomitant use of SSI-4 with lenvatinib and cabozantinib, tyrosine kinase inhibitors (TKIs) FDA-approved for HCC, in HCC cell lines in vitro and using HCC PDX in vivo mouse models. Our studies showed that the combination of the SCD1 inhibitor with both lenvatinib and cabozantinib showed a highly synergistic effect and no development of drug resistance i.e. durable response versus single TKI therapy. Ongoing mechanistic studies are examining whether known molecular targets of tested TKI’s such as VEGFR1, 2, and 3, PDGFRα, FGFR, KIT, and RET dominate in HCC drug resistance to lenvatinib and cabozantinib, and how the use of SSI-4 overcomes the phenomenon of resistance. Citation Format: Justyna J. Gleba, Aylin Alasonyalilar-Demirer, Matthew L. Pawlush, Ahmet Bilgili, Peyton G. Hickman, Kabir Mody, Lewis R. Roberts, Steven R. Alberts, Mark J. Truty, Tushar C. Patel, Han W. Tun, John A. Copland. Synergistic activity of SCD1 blockade in combination with tyrosine kinase inhibitors lenvatinib and cabozantinib in hepatocellular carcinoma (HCC). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5489.